Substituted propionic acids and processes of preparing the same



M... w. 13. ms 2,431,591

UNITED STATES PATENT OFFICE SUBSTITUTED PROPIONIC ACIDS AND PROCESSES OF PREPARING THE SAME Oscar H. Johnson, Medina, N. Y., assignor to Merck & 00., Inc., Railway, N. 3., a corporation of New Jersey No Drawing. Application November 19, 1946,-

Serial No. 710,945

5 Claims. (Cl. 260-4655) 1 2 This invention is concerned generally with In carrying out applicant's novel and improved novel chemical compounds, and with processes process, glyoxal semi-diethyl acetal is dissolved for preparing the same; more particularly it re.- in a solvent, such as ether, and the solution satulates to a-phenylacetamido-fi,fl-diethxy-proplrated with gaseous ammonia. The solvent and onic acid, an important intermediate in the syn- 5 excess ammonia are evaporated under reduced thesis of penicillin and other compounds. and pressure leaving the aldehyde-ammonia com-' with intermediate products and processes emound, a-amino-5,5-diethoxy-ethanol, as a waxy ployed in synthesizing the same from readily solid. Liquid hydrocyanic acid is added whereavailable starting materials. The new comupon the aldehyde-ammonia compound dissolves, pounds are further useful in the P epa 0f and the resulting solution is stirred for a Period serine, an important amino acid. They can also of at least abouthrs. The reaction mixture be used in studying and elucidating the structure is extracted with an organic solvent such as ether, of other more complex organic substances. the ether solution is filtered to remove insoluble Applicant has discovered that a-phenylimpurities, dried by conventional methods, as for acetamido-fi,B-diethoxy propionic acid can be 15 example, by means of anhydrous sodium sulfate, synthesized by reactions indictaed generically as and evaporated to produce a-amino-B.5-diethoxyfollows: propionitrile. The nitrile is conveniently purified NH J I kCIL-CHO cmoncm-cn-orr The reactions indicated above are conducted as by conversion to the hydrochloride using gaseous follows: glyoxal semi diethyl acetal (1) is rehydrogen chloride in alcohol solution; the crude acted with gaseous ammonia to produce m-amino- 5 a-amino-p,s-dietho xy propionitrile hydrochlopp-diethoxy-ethanol (2a) this compound is ride which precipitates is recovered by filtration, then treated with hydrocyanic acid and the and further purified by treatment with activated product treated with alcoholic HCl to produce charcoal in aqueous solution; the aqueous soluthe hydrochloride of a-amino-B,5-diethoxy-protion containing the partially purified hydr0ch10- pionitrile (2); this compound is reacted with ride is then treated with a mild alkaline mateaqueous barium hydroxide whereby the nitrile rial, such as sodium bicarbonate, and the resultgrouping is hydrolyzed to form barium a-flllllIlO- ing alkaline solution extracted with ether. The dB-diethoxy-propionate (3); this barium salt is ether extract, which contains the a-amino-fl,fithen treated in aqueous solution with carbon diethoxy-propionitrile' is then dried and evapodioxide, thus precipitating barium carbonate and rated and the amino-nitrile converted to the producing e-amino-B,fi-diethoxy-propionic acid hydrochloride as previously described. The (4) in aqueous solution; the solution of the latter hydrochloride of the amino-nitrile can be further compound is then reacted with phenylacetylpurified if, desired by recrystallization from a chloride to produce a-phenylacetamido-fi,p-disolvent, such as ethylene dichloride-petroleum ethoxy-propionic acid (5) ether.

When e-phenylacetamido-p,5-diethoxy-propi- The pure a-amino-,9,fi-diethoxy-propionitrile is onic acid (5) is heated with acetic anhydride the hydrolyzed by heating with an aqueous solution product obtained is 2-benzyl-4-ethoxymethyleneof an alkaline earth metal hydroxide, preferably 5(4) -oxazolone, which can be reacted with dwith barium hydroxide, to form the correspondpenicillamine to produce penicillin. ing alkaline earth metal salt of a-amino-Ap-diby the reaction.

ethoxy-propionic acid. This salt is converted to the free acid by treatment in aqueous solution with an alkaline earth precipitant, such as carbon dioxide, whereupon the alkaline earth metal carbonate precipitates and is separated from the solution containing the a-amino-fi,fl-diethoxypropionic acid by filtration or centriiugation.

The filtered aqueous solution containing the free a-amino acid is then reacted with successive portions of phenyl acetyl chloride and a mild alkaline agent, suchas sodium bicarbonate,

Example 1 Nineteen grams of glyoxalsemidiethylacetal were dissolved in 40 ml. of absolute ether. .This solution was cooled and saturated with gaseous ammonia. The ether and excess ammonia were then removed in vacuo leaving the aldehyde ammonia compound as a Waxy solid. 12 milliliters of liquid hydrocyanic acid were added and the resulting solution stirred for 20 hours. 150 milliliters of ether were added to the brown mixture and a small amount of insoluble material was removed by filtration. The filtrate was dried over anhydrous sodium sulfate and'the ether removed in vacuo. The residue was dissolved in 7 ml. of ethanol and dry hydrogen chloride passed into the solution with stirring. The solution I solidified upon cooling.

This crude a-amino-B,p-diethoxypropionitrile hydrochloride was dissolved in 100 ml. of water and filtered through a charcoal mat. Sodium bicarbonate was added to the filtrate until the mixture was slightly alkaline and then the mixture was extracted several times with ether. The combined ether extracts were dried over sodium sulfate andthen the mixture cooled while dry hydrogen chloride was introduced. The oil that separated crystallized upon scratching or seeding. This solid was removed by filtration, dissolved in 125 ml, of ethylene dichloride, filtered through a charcoal mat and then diluted 'with 50 ml. of petroleum ether. The pure e-amino-de-diethoxypropionitrile hydrochloride crystallized upon cooling; weight, 9.4 g.; M. P. 126-7 C. The filtrate was diluted with 200 ml. of petroleum ether to yield another crop of 1.3 g.; M. P.

125-6 C.; total yield, 10.7 g- (yield 38% of theory). Anal. Calcd. for CIH15N202C1: C. 43.19; H, 7.76; N, 14.39. Found: C, 43.30; H, 7.57; N, 14.43.

Example 2 To a solution of 5.7 g. of e-amino-flfi-diethoxypropionitrile hydrochloride in 190 ml. of water was added 11.4 g. of barium hydroxide monohy- The ether extract is dried and evapdrate. The mixture was warmed at C. for 12 hours and was then saturated with carbon dioxide and filtered. The filtrate was treated with successive portions of phenylacetyl chloride and sodium bicarbonate until phenylacetylation of the intermediate a-amino-fl,p-diethoxy-propionic acid was complete. The filtered solution was cooled and acidified with hydrochloric acid, then extracted with ether several times. The ether solution was dried over anhydrous sodium sulfate and the ether solution was then evaporated. The residual material was washed several times with petroleum ether to remove phenylacetic acid and was then recrystallized from ethylene dichloride-petroleum ether to produce 2.4 g. of substantially pure a-phenylacetamido-p,c-diethoxy-propionic acid; M. P. 112 C. (corrJj yield 28% of theory; Anal: Calcd. for C15H21O5NZ C, 61.01; H, 7.17; N, 4.74. Found: C, 61.20;

Modifications may be made in carrying out the present invention without departing from the spirit and scope thereof, and the invention is to be limited only by the appended claims.

I claim:

1. a-Amino-19, 8-diethoxy-propionitrile.

2. a-Amino-p,p-diethoxy propionitrile hydrochloride.

3. The process which comprises saturating an ether solution of glyoxal semidiethyl acetal with gaseous ammonia. evaporating the solvent and excess ammonia, stirring the waxy solid thus obtained with liquid hydrocyanic acid for a period of at least about 20 hours, and treating the resultin product in alcohol solution with gaseous hydrogen chloride to produce -amino-,6,B-diethoxypropionitrile hydrochloride.

4. The process which comprises saturating an ether solution of glyoxal semidiethyl acetal with gaseous ammonia, evaporating the solvent and excess ammonia, and stirring the waxy solid thus obtained with liquid hydrocyanic acid for a period of at least about 20 hours to produce m-amino- 5,,8-diethoxy-propionitrlle.

5. A compound of the formula:

cH-oH-cN C: i Q wherein Q is a radical selected from the class which consists of NHz, and NHz-HCl radicals.

OSCAR H. JOHNSON.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Name Date Kushner Feb. 12, 1946 OTHER REFERENCES Number 

